Small cell lung cancer (SCLC) claims more than 200,000 lives globally every year, and there are still no effective therapies in use for this fatal disease. Besides universal loss of the RB and P53 tumor suppressors required for SCLC initiation, the key pathways driving SCLC progression have still not been identified. Our long-term goal is to understand the molecular events that result in the aggressive itinerary of SCLC. Recent efforts to sequence the genomes of over 100 human SCLC tumors have identified rare oncogenic mutations and some regions undergoing amplification, but these analyses failed to shed light on a central oncogenic pathway that may drive the development of this cancer. Recently, the concept of non-oncogene addiction has emerged, which states that cancers may require certain active molecular pathways that are unmarked by mutations. Therefore, active but non-mutated signaling transductors such as kinases may play crucial roles in the development of cancers while remaining undiscovered by sequencing approaches. Using novel proteomic methodology, we recently obtained a first view of the active kinome of SCLC. Among active kinases in SCLC, Mek5 is particularly intriguing. Mek5 and its downstream target, Erk5, comprise a still poorly characterized signaling pathway; emerging evidence suggests that, similar to the more studied Mek1/2- Erk1/2 pathway, the Mek5/Erk5 axis may also regulate cell survival and cycling. Mek5 and Erk5 have never been studied in SCLC cells and little is still known about their role in cancer in general. Here we hypothesize that the Mek5/Erk5 module is crucial to the growth of SCLC. This hypothesis is supported by our preliminary observations that Mek5- or Erk5-deficient SCLC cells show severe growth deficiencies and increased apoptotic cell death. However, we lack a complete understanding of the requirement for this axis in SCLC development in the organismal context, and of how Mek5/Erk5 may be performing these roles. To investigate the role of the Mek5/Erk5 kinase axis in SCLC, we will utilize patient-derived xenografts (PDXs) and a genetically-engineered mouse model of SCLC. We first propose to determine if the Mek5/Erk5 axis is necessary for SCLC initiation and progression in mice in vivo. Second, we will investigate the role of Mek5/Erk5 in SCLC maintenance using genetic and pharmacological approaches. Third, we will perform structure-function studies and use advanced proteomics to investigate the mechanisms of action of Erk5 in SCLC cells. This study will characterize a novel non-mutated tumorigenic signaling pathway in the development of SCLC. We hope that a better understanding of the mechanisms underlying SCLC development will aid to identify novel therapeutic approaches for patient treatment.